Phase II Trial of Abraxane in Front Line Therapy of Hormone Refractory Metastatic Prostate Cancer

Taxanes are the most widely tested and effective chemotherapy drugs for hormone refractory
prostate cancer. Weekly paclitaxel was reported to produce 25-39% PSA responses in first
line and up to 33% in second line chemotherapy of patients with prostate cancer in early
clinical trials (1, 2). Paclitaxel activity in prostate cancer is schedule dependent, and
weekly paclitaxel was reported to produce highest response rates (1, 2). Docetaxel was
recently approved by the Food and Drug Administration for treatment of hormone refractory
metastatic prostate cancer, since it is the only chemotherapy drug with documented
improvement in survival in this group of patients. Docetaxel was associated with 45.8%
overall grade 3/4 toxicities and it has to be given with steroid pre-medication. This
regimen might be difficult to use in advanced prostate cancer patients that are often
elderly and with multiple co-morbid conditions.

ABI-007 [Abraxane™ (paclitaxel protein-bound particles for injectable suspension)
(albumin-bound)] is the first in its class of biologically interactive albumin-bound forms
of chemotherapy (3). This composition provides a novel approach of increasing intra-tumoral
concentration of the drug by a receptor-mediated transport process allowing transcytosis
across the endothelial cell wall, thereby breaching the blood/tumor interface. This
albumin-specific receptor mediated process involves the binding of a specific receptor
(gp60) on the endothelial cell wall, resulting in activation of a protein caveolin-1, which
initiates an opening in the endothelial wall with formation of a little caves or caveolae,
with transport of the albumin-bound chemotherapeutic complex via these caveolae to the
underlying tumor interstitium (4). A protein specifically secreted by the tumor (SPARC)
binds and entraps the albumin, allowing release of the hydrophobic drug to the tumor cell
membrane. ABI-007 is the first biologically interactive albumin-bound chemotherapy agent
leveraging this gp-60/caveolin-1/caveolae/Sparc pathway to increase intra-tumoral
concentration of the drug and reduce the amount of the toxic chemotherapy in normal tissue.

Preclinical studies comparing Abraxane to paclitaxel demonstrated lower toxicities, with a
maximum tolerated dose (MTD) approximately 50% higher for Abraxane (7) compared to
paclitaxel (11). At equal doses there was less myelosuppression and improved efficacy than
paclitaxel in a xenograft tumor model of human mammary adenocarcinoma. Clinical studies
confirmed improved toxicity profile and higher response rates, in metastatic breast cancer,
of Abraxane compared to cremophor EL paclitaxel (Taxol) (5, 8). The weekly regimen was
shown to be active even in patients with cancers refractory to paclitaxel, docetaxel or when
Abraxane was given after both agents (8).

Inclusion Criteria:

1. Histopathologically or cytologically proven adenocarcinoma of the prostate metastatic
to the bones or lymph nodes as documented by bone scan or CT scan with evidence of
progression despite standard hormonal management (orchiectomy, GNRH agonist, or GNRH
antagonist-hormone refractory). No major organ allowed

2. No prior chemotherapy

3. For patients who have been on anti-androgen therapy, patients must have progressive
disease after anti-androgen withdrawal (6 weeks biclutamide or nilutamide, 4 weeks
for flutamide).

4. PSA progression is defined as rising PSA.

Exclusion Criteria:

1. Active malignancy other than non-melanoma skin cancer within 5 years of enrollment.

2. Significant active medical illness which in the opinion of the investigator will
preclude treatment.

3. Brain metastasis, any non-bone metastasis except lymph node metastasis